Blood sugar loss may trigger Alzheimer's: study
LONDON, Dec. 24, 2008 (Reuters) — A slow, chronic reduction of
blood sugar to the brain could trigger some forms of Alzheimer's disease, U.S. researchers said on Wednesday.
A split-view image shows PET scans of a normal brain (L) and a brain with Alzheimer's disease. REUTERS/National Institute on Aging/Handout
The study of human and mice brains suggests a reduction of blood flow deprives energy to the brain, setting off a process that ultimately produces the sticky clumps of protein researchers believe is a cause of the disease, they said.
The finding could lead to strategies such as exercise, reducing cholesterol and managing blood pressure to keep Alzheimer's at bay, Robert Vassar and colleagues at Northwestern University's Feinberg School of Medicine in Chicago reported.
"This finding is significant because it suggests that improving blood flow to the brain might be an effective therapeutic approach to prevent or treat Alzheimer's," Vassar, who led the study, said in a statement.
"If people start early enough, maybe they can dodge the bullet."
Alzheimer's disease is incurable and is the most common form of dementia among older people. It affects the regions of the brain involving thought, memory and language.
While the most advanced drugs have focused on removing clumps of beta amyloid protein that forms plaques in the brain, researchers also are looking at therapies to address the toxic tangles caused by an abnormal build-up of the protein tau.
Vassar and colleagues analyzed human and mice brains to discover that a protein called elF2alpha is altered when the brain does not get enough energy. This boosts production of an enzyme that in turn flips a switch to produce the sticky protein clumps.
The finding published in the journal Neuron could lead to drugs designed to block the elF2alpha production that begins the formation of the protein clumps, also known as amyloid plaques, Vassar added.
"What we are talking about is a slow, insidious process over many years," he said. "It's so mild (people) don't even notice it, but it has an effect over time because it's producing a chronic reduction in the blood flow."
[The article published in Neuron]
doi:10.1016/j.neuron.2008.10.047
Phosphorylation of the Translation Initiation Factor eIF2a Increases BACE1 Levels and Promotes Amyloidogenesis
Tracy O'Connor1, Katherine R. Sadleir1, Erika Maus1, Rodney A. Velliquette1, Jie Zhao1, Sarah L. Cole1, William A. Eimer1, Brian Hitt1, Leslie A. Bembinster1, Sven Lammich2, Stefan F. Lichtenthaler2, Sébastien S. Hébert3, Bart De Strooper3, Christian Haass2, David A. Bennett4 and Robert Vassar1, Corresponding Author Contact Information, E-mail The Corresponding Author
1Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
2Department of Biochemistry, Laboratory for Neurodegenerative Disease Research, Center for Integrated Protein Science Munich and Adolf-Butenandt-Institute, Ludwig-Maximilians-University, 80539 Munich, Germany
3Department of Molecular and Developmental Genetics, VIB, Center for Human Genetics, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
4Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA
Accepted 17 October 2008.
Published: December 24, 2008.
Available online 24 December 2008.
Summary
ß-site APP cleaving enzyme-1 (BACE1), the rate-limiting enzyme for ß-amyloid (Aß) production, is elevated in Alzheimer's disease (AD). Here, we show that energy deprivation induces phosphorylation of the translation initiation factor eIF2a (eIF2a-P), which increases the translation of BACE1. Salubrinal, an inhibitor of eIF2a-P phosphatase PP1c, directly increases BACE1 and elevates Aß production in primary neurons. Preventing eIF2a phosphorylation by transfection with constitutively active PP1c regulatory subunit, dominant-negative eIF2a kinase PERK, or PERK inhibitor P58IPK blocks the energy-deprivation-induced BACE1 increase. Furthermore, chronic treatment of aged Tg2576 mice with energy inhibitors increases levels of eIF2a-P, BACE1, Aß, and amyloid plaques. Importantly, eIF2a-P and BACE1 are elevated in aggressive plaque-forming 5XFAD transgenic mice, and BACE1, eIF2a-P, and amyloid load are correlated in humans with AD. These results strongly suggest that eIF2a phosphorylation increases BACE1 levels and causes Aß overproduction, which could be an early, initiating molecular mechanism in sporadic AD.
Article Outline
Introduction
Results
Energy Deprivation Increases BACE1 Levels by a Translational Mechanism
Energy Deprivation Increases eIF2a Phosphorylation
Selective Inhibition of eIF2a Dephosphorylation Increases BACE1 Levels
Blocking eIF2a Phosphorylation by Constitutive Activation of the PP1/GADD43 Complex Prevents the Energy-Deprivation-Induced BACE1 Increase
Activation of the eIF2a Kinase PERK Is Necessary for the Energy-Deprivation-Induced BACE1 Increase
Glucose Deprivation Causes eIF2a Phosphorylation and Increases BACE1 Levels in Cultured Primary Neurons by a Posttranscriptional Mechanism
Selective Inhibition of eIF2a Dephosphorylation Increases BACE1 Level and Aß Production in Tg2576 Primary Neurons
Chronic Energy Inhibition Increases eIF2a Phosphorylation, BACE1 Levels, and Amyloidogenesis in Tg2576 Mice
Increased eIF2a Phosphorylation Correlates with Elevated BACE1 Levels in 5XFAD Transgenic Mice and Humans with AD
Discussion
Translational Control of BACE1: Potential Role of Cellular Stress
Chronic Neuronal Stress, eIF2a, and Amyloid Pathology
Experimental Procedures
Human Brain Tissue, Amyloid Loads, and Linear Correlations
Animals and Drug Treatments
Tissue Preparation for Biochemical Analysis
Human Aß40 ELISA
Amyloid Plaque Counts
Immunoblot Analysis
RNA Isolation and Real-Time PCR, and microRNA Analysis
Immunohistochemistry
Cell Line Cultures
Pulse-Chase
Neuronal Cultures
Statistical Analysis
Acknowledgements
Supplemental Data
References |
